The compound ezetimibe belongs to a class of lipid-lowering compounds that selectively inhibit the intestinal absorption of cholesterol and related phytosterols.
It is reported that ezetimibe has a mechanism of action that differs from those of other classes of cholesterol-reducing compounds, such as HMG-CoA reductase inhibitors, bile acid sequestrants (resins), fibric acid derivatives, and plant stanols. Ezetimibe reportedly does not inhibit cholesterol synthesis in the liver or increase bile acid excretion. Instead, it appears that ezetimibe localizes and acts at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. The result is a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood. Such a mechanism is complementary to that of HMG-CoA reductase inhibitors.
Ezetimibe is sold in the US under the brand name Zetia®, which is available as a tablet for oral administration containing 10 mg of ezetimibe and the following inactive ingredients: croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, povidone USP, and sodium lauryl sulfate NF.
WO 2006/060808 A1 describes ezetimibe polymorphs and processes for preparing same. In particular, this reference describes processes for preparing crystalline forms of ezetimibe, such as ezetimibe form A or form B by precipitating ezetimibe from selected solvents. The micronized ezetimibe particles of WO 2006/060808 have a small particle size and a high specific surface area.
EP 1 353 696 B1 describes a specific composition comprising 10% ezetimibe, 55% lactose monohydrate, 20% microcrystalline cellulose NF, 4% povidone USP, 8% croscarmellose sodium NF, 2% sodium lauryl sulfate and 1% magnesium stearate. The composition of EP 1 353 696 B1 does not contain starch and does not contain starch paste.
WO 95/08532 A1 and WO 95/35277 A1 disclose substituted acetidinone compounds useful as hypocholesterolemic agents. Both documents disclose a composition comprising active compound, lactose, corn starch as a 10% paste in purified water, corn starch and magnesium stearate. However, the amount of active compound in the compositions of these documents is greater than 30 wt-%, and the concentration of lactose is less than 50%.
It is desirable that the ezetimibe containing pharmaceutical compositions show a rather fast dissolution and optionally quick disintegration. It is an object of this invention to provide ezetimibe containing compositions having favourable properties.